The community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) epidemic poses a significant health and economic burden. As CA-MRSA is now the predominant MRSA clone in the community and in many healthcare settings, clinicians and infection prevention specialists face new challenges. The community has become an important and expanding reservoir for the spread of virulent CA-MRSA strains into hospitals, likely increasing the severity of nosocomial MRSA infections. Efforts are needed to mitigate the spread of MRSA in the community and decrease the burden of CA-MRSA infections. Households are significant reservoirs for MRSA transmission and important targets for MRSA eradication. Our prior study demonstrated that a one-time decolonization regimen performed by all household members reduced (but did not eliminate) the incidence of skin and soft tissue infection (SSTI) in index patients and household contacts. Given the widespread dissemination of CA-MRSA and risk for ongoing exposure, a periodic approach to personal decolonization may provide sustained protection against CA-MRSA reacquisition. Additionally, environmental surfaces in households of patients with MRSA infection are frequently and persistently contaminated with MRSA; thus, decontamination of household surfaces may limit the acquisition and spread of MRSA. Pediatric patients with CA-MRSA infection and their household members will be recruited to participate in a pragmatic comparative effectiveness trial evaluating personal and household environmental hygiene strategies to decrease the burden of CA-MRSA disease. Specifically, all participants (index patients and their household contacts) will perform a baseline 5-day MRSA decolonization protocol consisting of enhanced hygiene measures, application of mupirocin antibiotic ointment to the anterior nares twice daily, and daily body washes with chlorhexidine antiseptic. Following the 5-day baseline decolonization regimen, households will be randomized to one of three intervention groups: 1) Periodic personal decolonization performed by all household members, to include chlorhexidine body washes twice weekly for 3 months and application of intranasal mupirocin for 5 consecutive days each month for 3 months; 2) Household environmental hygiene, including targeted cleaning of household surfaces and laundering of bed linens, weekly for 3 months; and 3) Integrated periodic personal decolonization and household environmental hygiene for 3 months. Households will be followed for 9 months to measure the prevalence of MRSA colonization in the participants and the household environment and to document the incidence of recurrent SSTI. Molecular strain typing will be performed on all recovered MRSA isolates to illuminate transmission dynamics. Each recovered MRSA isolate will be tested for resistance to mupirocin, chlorhexidine, and systemic antibiotics. The proposed trial will identify best strategie for curtailing the incidence of CA-MRSA infections, thus reducing healthcare utilization for CA-MRSA treatment, potentially preventing additional migration of virulent CA-MRSA strains into hospitals.